The mucopolysaccharidoses are lysosomal disorders that progressively affect most organ systems in the body usually beginning in childhood. Recent treatment advances have produced amelioration of some of these malfunctions, but notably brain and bone have been difficult to treat. This research addresses the brain abnormalities in the MPS disorders about which little is known. The objectives of this research are: 1) to identify abnormalities of central nervous system (CNS) structure and function as well as to measure quality-of-life (QOL) in both treated and untreated patients with MPS disorders over time. We will accomplish this through longitudinal studies of enrolled patients in core centers in North America that constitute the Lysosomal Disease Network (LDN). We hypothesize that specific and localized neuroimaging and neuropsychological findings and their relationship will be distinct for each MPS disorder. Further, without treatment, functions will decline and structure will change over time in a predictable fashion, and will be related to locus of abnormality and stage of disease 2) to develop quantitative measurements of change; including direct measurement of neuropsychological function, surrogate MRI markers, and biomarkers to measure stage of disease and treatment outcomes. 3) to examine the degree to which independent variables ( such as age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, sensory abnormalities and others) have an impact on both functional and structural outcome brain variables as well as quality-of-life. 4) to examine how treatments such as ERT, HSCT, substrate reduction and other palliative and rehabilitation therapies differentially affect CNS structure and functions and quality of life (QOL). Methods: Over the first two years 70 children will be enrolled and followed in this study from 8 centers over five years; 30 MPS I, 20 MPS II, and 20 MPS VI. Each child will be seen yearly for a total of at least 3 or possibly 4 follow-up visits within the five year period. A quantitative neuroimaging and neuropsychological protocol will be used to collect data as well as relevant medical and environmental variables that may impact these measures. A new biomarker that may be sensitive to change will also be collected. Data will be analyzed to determine the locus of central nervous system abnormality, the sensitivity of measures to change and disease progression, and to identify the variables that contribute to these outcomes.